Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.

OBJECTIVE: To evaluate the 24-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly or as needed (pro re nata [PRN]) in patients with neovascular age-related macular degeneration (wet AMD). DESIGN: Twenty-four-month, multicenter, randomized, double-masked, active treatment-controlled phase 3 trial. PARTICIPANTS: Patients (n = 1098) ≥ 50 years of age with treatment-naïve subfoveal wet AMD. METHODS: Patients were randomized to receive intravitreal injections of ranibizumab 0.5 mg or 2.0 mg monthly or PRN after 3 monthly loading doses. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean change in best-corrected visual acuity (BCVA) from baseline at month 12. Key secondary end points included mean change in BCVA from baseline at month 24, proportion of patients who gained ≥ 15 letters in BCVA, mean number of ranibizumab injections, and mean change in central foveal thickness from baseline over time by spectral-domain optical coherence tomography. Ocular and systemic safety events also were evaluated through month 24. RESULTS: At month 24, the mean change from baseline in BCVA was (letters) +9.1 (0.5 mg monthly), +7.9 (0.5 mg PRN), +8.0 (2.0 mg monthly), and +7.6 (2.0 mg PRN). The change in mean BCVA from month 12 to 24 was (letters) -1.0, -0.3, -1.2, and -1.0, respectively. The proportion of patients who gained ≥ 15 letters from baseline in BCVA at month 24 was 34.5%, 33.1%, 37.6%, and 34.8%, respectively. The mean number of ranibizumab injections through month 24 was 21.4, 13.3, 21.6, and 11.2, respectively; 5.6 and 4.3 mean injections were required in year 2 in the 0.5 mg and 2.0 mg PRN groups, respectively. The average treatment interval in the 0.5 mg PRN group was 9.9 weeks after 3 monthly loading doses, and 93% of these patients did not require monthly dosing. Ocular and systemic safety profiles over 2 years were similar among all 4 treatment groups and were consistent with previous ranibizumab trials in AMD. CONCLUSIONS: At month 24, mean BCVA improvements were clinically meaningful and similar among all 4 ranibizumab treatment groups. The 0.5 mg PRN group achieved a mean gain of 7.9 letters at month 24 with an average of 13.3 injections (5.6 injections in year 2). No new safety events were identified over 24 months.

Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 study.

Background: Gene therapy, successfully used in rare, monogenetic disorders, may prove to be a durable management approach for common, polygenetic conditions, including neovascular age-related macular degeneration (nAMD). Repeated injections, oftentimes monthly, and possibly for decades, of vascular endothelial growth factor antagonists (anti-VEGF), is the standard for nAMD. We hypothesised that an in-office, intravitreal administration of ixoberogene soroparvovec (ixo-vec, formerly ADVM-022), a single-dose gene therapy encoding for the proven anti-VEGF protein, aflibercept, would transform retinal cells to continually produce aflibercept to minimise treatment burden in nAMD. Methods: In this two-year, open-label, prospective, multicentre phase 1 study, patients with nAMD responding to anti-VEGF were assigned to four cohorts differing by ixo-vec dose (2 × 1011 vs 6 × 1011 vector genomes (vg/eye)) and prophylactic steroids (oral prednisone vs topical difluprednate). The primary outcome was the type, severity, and incidence of ocular and systemic adverse events (AEs); secondary endpoints included vision, central subfield thickness (CST), and the number of supplemental injections. This study was registered with ClinicalTrials.gov, NCT03748784. Findings: Thirty patients with nAMD were enrolled between November 14, 2018 and June 30, 2020 at nine study sites in the United States. No systemic ixo-vec related AEs were noted. Across both dose groups the most common adverse event was anterior chamber cell, which was reported in 11 participants in the 6 × 1011 dose group and in 7 participants in the 2 × 1011 dose group; intraocular inflammation was responsive to topical corticosteroids, with no anterior chamber cells or vitreous cells observed in 2 × 1011 vg/eye patients at the end of the study. Vision and CST remained stable throughout two years with annualised anti-VEGF injections reduced by 80% (10.0 mean annualised anti-VEGF injections to 1.9) in 2 × 1011 vg/eye and 98% (9.8 mean annualised anti-VEGF injections to 0.2) in 6 × 1011 vg/eye cohorts. Interpretation: Ixo-vec was generally well-tolerated, maintained vision, and improved anatomical outcomes in nAMD, with a substantial reduction in anti-VEGF injections. A single administration of an in-office gene therapy, with vectorised protein with an already established clinical benefit, has the potential to revolutionise the management of common ocular disorders requiring ongoing, frequent therapeutic interventions. Funding: Adverum Biotechnologies.

Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.

OBJECTIVE: To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular age-related macular degeneration (wet AMD). DESIGN: A 24-month, phase III, randomized, multicenter, double-masked, dose-response study. PARTICIPANTS: Patients aged ≥ 50 years with subfoveal wet AMD. METHODS: Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥ 15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data. RESULTS: At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥ 15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was -172.0 µm, -161.2 µm, -163.3 µm, and -172.4 µm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups. CONCLUSIONS: At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Cataract surgery cost utility revisited in 2012: a new economic paradigm.

OBJECTIVE: To assess the 2012 cost utility of cataract surgery in the United States and to compare 2012 cost-utility data with those from 2000. DESIGN: Value-Based Medicine (Flourtown, PA), patient preference-based, comparative effectiveness analysis and cost-utility analysis using 2012 real United States dollars. PARTICIPANTS: Previously published Patient Outcomes Research Team Study data and time tradeoff utilities obtained from patients with vision loss. Visual acuity measurements from patients wtih untreated cataract were used as controls. INTERVENTION: Thirteen-year, average, first-eye and second-eye cataract surgery cost-utility analysis using the societal and third-party insurer cost perspectives. MAIN OUTCOME MEASURES: Patient value gain in quality-adjusted life years (QALYs) and percent gain in quality of life as well as the cost-utility ratio using the dollars expended per QALY gained. Patient and financial value outcomes were discounted at 3% annually with net present value analysis. RESULTS: First-eye cataract surgery conferred 1.6212 QALYs over the 13-year model, a 20.8% quality-of-life gain. Bilateral cataract surgery conferred 2.8152 QALYs over 13 years, a 36.2% improvement in quality of life. The direct ophthalmic medical cost for unilateral cataract surgery in 2012 United States nominal dollars was $2653, an inflation-adjusted 34.2% less than in 2000 and 85% less than in 1985. The 2012 inflation-adjusted physician fee was 10.1% of that in 1985. The 13-year societal cost perspective, financial return on investment (ROI) for first-eye cataract surgery was $121,198, a 4567% gain. The third-party insurer cost perspective average cost-utility ratio was $2653/1.6212 = $1636/QALY for unilateral cataract surgery, whereas the societal cost perspective average cost-utility ratio was -$121,198/1.6212 = -$74,759/QALY. The net 13-year $123.4-billion financial ROI from a 1-year cohort of cataract surgery patients was accrued: Medicare, $36.4 billion; Medicaid, $3.3 billion; other insurers, $9.6 billion; patients, $48.6 billion; and increased United States national productivity, $25.4 billion. CONCLUSIONS: Cataract surgery in 2012 greatly improved quality of life and was highly cost effective. It was 34.4% less expensive than in 2000 and 85% less expensive than in 1985. Initial cataract surgery yielded an extraordinary 4567% financial ROI to society over the 13-year model.

Overview of ocular anesthesia: past and present.

PURPOSE OF REVIEW: Many choices of ocular anesthetic techniques are available to the ophthalmologist. This study reviews currently used techniques of topical, subconjunctival and regional block anesthesia used in ophthalmic procedures. RECENT FINDINGS: The choices of anesthetics that are available are considered and a new ocular anesthetic gel is described that provides sustained ocular surface anesthesia, minimal side-effects and may also have antimicrobial properties. SUMMARY: Consideration of ocular anesthetic techniques and anesthetic choice plays a critical role for the success and safety of ophthalmic surgery.

Vitreous nonsteroidal antiinflammatory drug concentrations and prostaglandin E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.1%.

PURPOSE: To assess vitreous concentrations of nonsteroidal antiinflammatory drugs (NSAIDs) and prostaglandin E(2) in patients treated with NSAIDs before vitrectomy. METHODS: This was an investigator-masked, randomized, multicenter study. Patients received ketorolac 0.4% 4 times a day, bromfenac 0.09% 2 times a day, nepafenac 0.1% 3 times a day, or no NSAID for 3 days before surgery. Nonsteroidal antiinflammatory drugs and prostaglandin E(2) levels were determined in vitreous samples collected at the beginning of surgery. RESULTS: Thirty-one patients were included in the analyses. The mean (SD) vitreous concentrations were as follows: ketorolac 2.8 (3.2) ng/mL, bromfenac 0.96 (0.31) ng/mL, nepafenac 1.1 (0.6) ng/mL, and amfenac 2.0 (0.8) ng/mL aligned with the initial concentrations of the topical NSAIDs. Mean (SD) vitreous prostaglandin E(2) levels of the control patients and those treated with ketorolac 0.4%, bromfenac 0.09%, or nepafenac 0.1% were 270.6 (91.7) pg/mL, 189.6 (50.2) pg/mL, 247.2 (38.3) pg/mL, and 267.7 (99.7) pg/mL, respectively. Patients treated with ketorolac 0.4% had significantly lower prostaglandin E(2) levels than those treated with no NSAID (P = 0.047) or nepafenac 0.1% (P = 0.028). CONCLUSION: All three NSAIDs penetrated into the vitreous cavity. Topical therapy with ketorolac may lower preoperative vitreous prostaglandin E(2) levels, which may have a clinical impact on the management of prostaglandin-mediated diseases, including cystoid macular edema.

Cost-utility analysis of cataract surgery in the United States for the year 2018.

PURPOSE: To perform a cost-utility analysis of 2018 United States real dollars for cataract surgery. SETTING: Center for Value-Based Medicine, Hilton Head, South Carolina, USA. DESIGN: Cost-utility analysis. METHODS: A base-case 14-year cost-utility model using the ophthalmic cost perspective was used. Third-party insurer and societal cost perspectives were also analyzed. Patient outcomes and costs were discounted with net present value analysis at 3% a year. RESULTS: First-eye cataract surgery resulted in a 2.523 quality-adjusted life-year (QALY) gain, a 33.3% patient value gain, and 25.5% quality-of-life gain. Bilateral surgery yielded a 44.1% patient value gain, while second-eye cataract surgery alone conferred an 8.1% value gain. First-eye cataract surgery resulted in a gain of 2.52 QALYs, while second-eye surgery added an incremental gain of 0.81 QALYs. The ophthalmic-cost-perspective average cost-utility ratio was $2526/2.523 = $1001/QALY for first-eye cataract surgery. The societal-cost-perspective average cost-utility ratio was -$370 018/2.523 = -$146 629/QALY. The second-eye ophthalmic-cost-perspective cost-utility ratio was $2526/0.814 = $3101/QALY, while the ophthalmic-cost-perspective cost-utility ratio for bilateral cataract surgery was $5052/3.338 = $1514/QALY. The 14-year U.S. 2018 real-dollar societal-cost-perspective net return on investment for first-eye cataract surgery was $370 018 above the $2526 cost expended for cataract surgery. CONCLUSIONS: Cataract surgery in both the first eye and second eye, when analyzed by standard health economic methodologies, is highly cost-effective. Cataract surgery in 2018 was 73.7% more cost-effective than in 2000.

Lidocaine hydrochloride gel for ocular anesthesia: results of a prospective, randomized study.

BACKGROUND AND OBJECTIVE: This study evaluates the effectiveness of Akten (Akorn, Inc., Buffalo Grove, IL), a novel ophthalmic gel anesthetic agent for complete ocular anesthesia. PATIENTS AND METHODS: This study was conducted as a prospective, randomized, double-blinded, multicenter Phase III clinical trial to evaluate Akten gel. The study had four cohorts of subjects who received sham gel, Akten 1.5%, Akten 2.5%, and Akten 3.5%, respectively. Subjects were assessed for achievement of anesthesia at defined time intervals and questioned for "pain" or "no pain" following pinching of the conjunctiva with 0.3-mm forceps at predetermined intervals. RESULTS: A total of 209 subjects were entered into the study. The percentages of patients achieving the primary endpoint (ie, anesthesia within 5 minutes) were as follows: 22% for sham, 88% for Akten 1.5%, 89% for Akten 2.5%, and 92% for Akten 3.5%, respectively. Safety measures including corneal staining, conjunctival hyperemia, and eye pain with administra-tion were low and comparable in all cohorts. CONCLUSION: Akten gel appears to be an effective and safe ocular anesthetic. All doses were well tolerated and no dose-related corneal toxicity was observed.

Changing trends in the microbiologic aspects of postcataract endophthalmitis.

OBJECTIVE: To analyze the microbiologic spectrum and in vitro susceptibility profiles over the last 11 years of organisms isolated from the vitreous of patients with endophthalmitis following cataract surgery. METHODS: Records of 497 consecutive patients treated at 1 institution for clinically suspected endophthalmitis following cataract surgery from July 1989 through June 2000 were reviewed. Results of microbiologic culture and in vitro antibiotic susceptibility testing from the periods 1989 to 1994 and 1995 to 2000 were compared. RESULTS: Between the 2 periods, there was a significant increase in the incidence of gram-positive bacteria (92%-97% of bacterial isolates). There was a significant increase in resistance among all bacterial isolates to ciprofloxacin (23%-37%; P = .02). There was increased resistance among coagulase-negative staphylococci to both ciprofloxacin (20%-38%) and cefazolin (19%-40%). Resistance to bacitracin, trimethoprim-sulfamethoxazole, and vancomycin remained unchanged. Vancomycin retained in vitro efficacy against more than 99% of gram-positive bacteria. Ceftazidime was effective against 100% of gram-negative bacteria tested. CONCLUSIONS: The spectrum of pathogens causing postcataract endophthalmitis is changing, and resistance to antibiotics used for its prophylaxis has grown. These findings may affect the empirical treatment of postcataract endophthalmitis, as well as the use and choice of antibiotics in patients undergoing cataract surgery.

Baseline Predictors of 12-Month Treatment Response to Ranibizumab in Patients With Wet Age-Related Macular Degeneration.

PURPOSE: To identify baseline characteristics predictive of visual acuity (VA) outcomes at month 12 (M12) and treatment frequency in the first 12 months of the phase III HARBOR study. DESIGN: Retrospective, exploratory analysis of multicenter randomized controlled trial data. METHODS: setting: Randomized, multicenter. STUDY POPULATION: Patients aged ≥50 years with subfoveal wet age-related macular degeneration (AMD) who had best-corrected VA (BCVA) values measured at baseline and M12. INTERVENTION: Intravitreal ranibizumab 0.5 mg administered monthly (n = 249) or as needed (PRN) after 3 monthly loading doses (n = 251). MAIN OUTCOME MEASURES: BCVA change from baseline at M12, percentage of patients who gained ≥15 letters (3 lines) in BCVA from baseline at M12, and percentage of patients who achieved ≥20/40 vision (Snellen) at M12 served as the basis for analyzing baseline predictors of observed VA outcomes in the monthly and PRN groups. Total number of ranibizumab PRN injections in the first 12 months was also evaluated. Only variables that were statistically significant (P < .05) remained in the final statistical models. RESULTS: Baseline predictors of BCVA change from baseline at M12 and/or percentage of 3-line gainers included lower BCVA, younger age, smaller total choroidal neovascularization (CNV) leakage area, smaller area of occult CNV, and presence of subretinal fluid (SRF). Baseline predictors of ≥20/40 vision at M12 included higher BCVA, smaller total CNV leakage area, and presence of SRF. SRF thickness >118.25 µm at baseline predicted requiring more ranibizumab injections in the first 12 months of treatment. CONCLUSIONS: Select baseline characteristics have predictive value for visual prognosis and treatment frequency in ranibizumab-treated patients with wet AMD.

Endophthalmitis: a reappraisal of incidence and treatment.

PURPOSE OF REVIEW: The current publications that address either the incidence or treatment of endophthalmitis are reviewed. RECENT FINDINGS: A large body of published research has recently addressed the issue of potential increases in the incidence of endophthalmitis, especially postcataract endophthalmitis. Additional studies have evaluated relatively new antibiotics and their potential effect on the prevention and treatment of endophthalmitis. SUMMARY: Although there appears to be a renewed effort to report the incidence and theorized risk factors for postcataract endophthalmitis, there are wide discrepancies in the rate and potential causes of postoperative endophthalmitis. In regards to endophthalmitis treatment, helpful findings regarding the potency of newer antibiotics and the appropriateness of subconjunctival antibiotics are reviewed.

Update on treatment strategies for bleb-associated endophthalmitis.

PURPOSE OF REVIEW: Visual preservation in the setting of bleb-associated endophthalmitis has been difficult with existing management strategies. In this article, established findings are compared and potential new treatments that may improve visual outcomes in bleb-associated endophthalmitis are evaluated. RECENT FINDINGS: Recent reports have contributed to the existing database of results from bleb-associated endophthalmitis. New systemic antibiotics and novel surgical techniques are also described. SUMMARY: More options are now available to treat bleb-associated endophthalmitis. No one treatment paradigm is definitively superior in producing desired visual outcomes.

Advances in knowledge and treatment: an update on endophthalmitis.

PURPOSE OF REVIEW: In an area of increased willingness to perform surgery as surgical techniques are refined, comes the unavoidable complication of endophthalmitis. Because complete elimination of postsurgical endophthalmitis appears unattainable, strategies directed at optimal prevention, diagnosis, and management are constantly pursued. RECENT FINDINGS: Recent reports of the various aspects of endophthalmitis were analyzed from the leading peer-reviewed ophthalmic journals. SUMMARY: The author reviews the recent work concerning the factors that affect visual prognosis in postsurgical endophthalmitis.

Cost-effectiveness of ocular interventions.

The cost-effectiveness of ophthalmic interventions has become increasingly important as the US health care budget continues to grow. During the past two decades, a methodology rooted in utility analysis has provided a way to objectively assess the value of an intervention for a specific disease. Specifically within the field of ophthalmology, there is a growing body of literature on utility analysis using patient preference-based outcomes for ophthalmic disease. This has led the way to combining costs with utility values to derive a cost-utility analysis, or cost-effectiveness, for a given ophthalmic procedure. This article outlines this methodology, provides a reference-case example for initial cataract surgery, and describes a comparative study of the value associated with interventions within the field of ophthalmology and across other medical specialties.

Cost-utility analysis of cataract surgery in the second eye.

OBJECTIVE: To perform a reference case cost-utility analysis of second-eye cataract surgery by using the current literature on cataract outcomes and complications. DESIGN: Computer-based econometric modeling. METHODS: Visual acuity data of patients treated and observed over a 4-month postoperative period were obtained from the U.S. National Cataract Patient Outcomes Research Team report. The results from this prospective study were combined with those of other studies that investigated the complication rates of cataract surgery to complete the cohort of patients and outcomes. These synthesized data were incorporated with time trade-off utility values, which accounted for prior successful cataract surgery in the fellow eye. Cost-utility determinations were made with decision analysis, and present value modeling was used to account for the time value of money and health state consequences. MAIN OUTCOME MEASURES: The number of quality-adjusted life-years (QALYs) gained was calculated for the study group undergoing second-eye cataract surgery, assuming that the postoperative vision in the second eye was equivalent to the vision in the first eye after surgery (20/27). This was divided into the cost of the procedure to find the number of year 2001 nominal U.S. dollars spent per QALY gained. RESULTS: Second-eye cataract surgery, as compared with unilateral pseudophakia, resulted in a mean gain of 1.31 undiscounted QALYs per patient treated. A 3% annual discount rate, dependent on the duration of benefit, was used, yielding 0.92 discounted QALYs gained over a 12-year life expectancy. The mean discounted cost of treatment for each patient totaled 2509 US dollars. The cost divided by the QALYs gained (benefit) resulted in 2727 US dollars per QALY gained for this procedure. Sensitivity analysis varying costs and utility values revealed a range from 2045 US dollars to 3649 US dollars per QALY gained. CONCLUSIONS: Second-eye cataract surgery is an extremely cost-effective procedure when compared with other interventions across medical specialties. The cost-effectiveness of second-eye surgery diminishes only slightly from the 2023 US dollars per QALY gained from first-eye cataract surgery. This suggests that patients with good vision in one eye and visual loss from cataract in the fellow eye derive substantial benefit from cataract extraction.

CME review: A cost-utility analysis of laser photocoagulation for extrafoveal choroidal neovascularization.

PURPOSE: The purpose of this study was to perform a reference case (average case), cost-utility analysis of laser photocoagulation for extrafoveal choroidal neovascularization associated with age-related macular degeneration using a model incorporating patient preferences. METHODS: Visual acuity data for patients treated and observed over a 5-year period were obtained from previously reported studies by the Macular Photocoagulation Study Group. The results from this prospective, randomized trial were incorporated in a cost-utility model using time-trade-off utility analysis and decision analysis with Markov modeling according to the recommendations of the Panel on Cost-Effectiveness in Health and Medicine. Expenditures and health care benefits were each discounted at a 3% yearly rate. RESULTS: Laser photocoagulation therapy for extrafoveal choroidal neovascularization in age-related macular degeneration, compared with observation, resulted in a mean gain of 0.0740 quality-adjusted life-year per patient treated. The mean cost of treatment for the average patient totaled 1,715 US dollars. The cost divided by the health care benefit resulted in 23,176 year 2001 US dollars per quality-adjusted life-year gained for this procedure for a reference case. Sensitivity analyses, varying the cost, utility values, and discount parameters, resulted in dollars per quality-adjusted life-year gained ranging from 16,117 to 49,766 US dollars. CONCLUSION: Laser photocoagulation for extrafoveal choroidal neovascularization associated with age-related macular degeneration appears to be cost-effective when compared with interventions across multiple medical specialties.